ABSTRACT Chronic kidney disease is a progressive and heterogeneous condition that affects 10% of individuals worldwide, and a cause of premature cardiovascular disease and death. Little is known about the mechanisms leading to its development and predisposition. Despite the strong evidence for a role of ancestry in chronic kidney disease susceptibility, few studies have leveraged ancestry for gene discovery. Hispanics are an understudied minority group that is comprised of many overlapping ancestral groups (Amerindian, West African, European). Hispanics have a high prevalence of increased albuminuria and end-stage renal disease, which has been associated with their Amerindian ancestry. We propose to identify ancestry-specific loci, and their corresponding rare and common genetic variants, that explain the higher susceptibility for chronic kidney disease in Hispanics. We will use novel admixture mapping approaches to map genomic segments and variants inherited from the ancestral population with the higher disease variant frequency (Aim 1), followed by fine-mapping and validation of associations in ancestry-specific cohorts (Hispanics, American Indians, European and West Africa ancestries) (Aim 2). We will leverage data from the large population-based Hispanic Community Health Study/Study of Latinos for gene discovery, and propose to fine-map Amerindian loci using a combination of genotyping and targeted sequencing. To gain insights into the functional roles of identified genes, we will prioritize variants for experiments using in vitro and mouse model systems for transgenic and gene targeting studies (Aim 3). This proposal leverages ancestry to identify loci for kidney traits in Hispanics, and uniquely complement large ongoing genome wide association approaches. Our results will provide clues to racial/ethnic disparities in disease risk, and improve understanding of the biological pathways leading to chronic kidney disease. Ultimately this research could inform personalized medicine and improve public health.